Estrogen plays an important role in protecting the health of women such as protecting and maintaining cardiovascular health, bone mass, and mental cognition. However, normal ageing process results in lower levels of estrogen in women and the estrogen level may be significantly reduced upon entering menopause or upon surgical removal of the uterus and/or ovaries, for which reason those women risk the development of cardiovasculary diseases, bone mineralisation and/or poor mental cognition. Loss of bone mineral density is the key indicator of osteoporosis.
Reduced estrogen levels have also been implicated in the development of urinary incontinence as a result of the effect of the loss or estrogen on the smooth muscle cells of the urethra. Reduced estrogen levels may also be implicated in significant weight and fat mass gain in postmenopausal women.
Hormone replacement therapy has aimed to improve the quality of life of women during this natural ageing process to alleviate symptoms associated with this time of transition and to reduce the likelihood or slow the progression of disorders and diseases associated with reduced estrogen activity.
One principal aim of hormone replacement therapy is to restore levels of the sex steroid hormones in naturally or prematurely pre-menopausal, menopausal and post-menopausal women or to establish these levels in hypogonadal females.
One form of hormone replacement therapy relates to monotherapy, also referred to as unopposed therapy, wherein the woman is treated with estrogens alone. However, exogenous estrogens stimulate the proliferation of the endometrium, which may result in in the development of hyperplasia, a risk factor for endometrial cancer.
A second form of hormone replacement therapy relates to combination therapy, also referred to as opposed therapy, wherein the woman is treated with a combination of an estrogen and a progestagen. Advantageously, the progestogen protects the endometrium from hyperplasia.
However, the use of natural progesterone in combination therapy is limited by the low bioavailability of natural progesterone, even in micronized form. Significantly, it has been found that combination therapy comprising the use of drospirenone as a progestogen, is remarkably effective. Drospirenone (drospirenone), a 17-α-spirolactone derivative, is a synthetic progestagen that has a surprisingly similar physiological profile to progesterone yet notably better bioavailability. It is the first synthetic progestagen to have a progesterone-like pharmacological profile in that it has antiestrogenic, antiandrogenic and anti-mineralcorticoid activity.
The progestogenic activity of drospirenone and its consequent utility as a contraceptive agent at dosage levels of 0.5-50 mg is disclosed in DE 30 22 337. The anti-mineralcorticoid activity of drospirenone limits the increase in weight gain that is observed in women taking estrogens by reduction of the estrogen-induced sodium and water retention. The anti-mineralcorticoid effect is also known to have beneficial and preventive effects on hypertension. The anti-androgenic activity of drospirenone may suppress unwanted symptoms such as acne and changes in hair pattern, hair distribution, and hair growth such as in hirsutism, by inhibiting androgenic receptors in the skin. The pharmacological activities of drospirenone is described in Krattenmacher, Rolf, Contraception (62) 2000, pp 29-38; Drospirenone: pharmacology and pharmacokinetics of a unique progesterone. The activity of drospirenone is further described in Drugs of the Future 2000, 25(12), pp 1247-1256.
Drospirenone is also known from DE 26 52 761 in which its use as a diuretic is disclosed.
The use and role of progestogens in opposed forms of hormone replacement therapy has been studied by the scientific community (Lobo R. A., 1992; Sobel N. B., 1994) as have been regimens comprising estrogens and progestogens (Corson S. L., 1993, ones K. P., 1992).
Various regimens for hormone substitution have been disclosed. For example the use of a preparation for hormone substitution therapy comprising at least one progestagen and at least one estrogen wherein the estrogen dose varies with a periodicity such that blood loss is substantially avoided is disclosed in WO 95/07081. Furthermore, a regimen involving interrupted administration of progestin in the presence of continuous estrogen is disclosed (Casper R. F. et al., Am J Obstet. Gynecol. vol 168, no 4, p 1188-1983).
The use of a therapeutic gestagen such as drospirenone, possibly in combination with an estrogen for the treatment of Premenstrual Dysphoric Disorders (PMDD) is disclosed in WO 98/27929.
Also various pharmaceutical compositions comprising drospirenone have been reported, for example, a pharmaceutical composition comprising a combination of ethinyl estradiol and drospirenone for use as a contraceptive is disclosed in WO 01/12801.
Estrogen sulphamates, such as estradiol sulphamate, may be viewed as prodrugs, which, upon enzymatic hydrolysis by sulphatases in vivo, are split into the estrogen, such as estradiol, and a sulphamic acid. The use of estrogen sulphamates for oral discontinuous application for hormone replacement therapy is disclosed in WO 00/06175. The discontinuous method of administration is such that the administration can take place at intervals ranging from 2 to 40 days. WO 00/06175 also relates to the additional administration of gestagens, preferably continuously in the form of an implant or in the form of an intrauterine releasing system.
Estradiol sulphamates were first disclosed in WO 93/05064 in connection with the findings that estrone sulphamates showed excellent sulphatase inhibiting activity for which reason it may be used in the treatment of estrone dependent rumors, especially breast cancer.
The invention relates to the use of a combination of drospirenone and an estradiol sulphamate in hormone replacement therapy.